Appetite-suppressant drugs and the risk of primary pulmonary hypertension

Authors: Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, et
al (for the International Primary Pulmonary Hypertension Study Group).
Source: New England Journal of Medicine. 335:609-16.
August 29, 1996.
Institutions: McGill University and multiple institutions in
the United States and Europe.
Financial support: Medical Research Council of Canada, Institut
de Recherches Internationales Servier and Ministry of Public Health and
Environment of Belgium.

Summary

Background

Appetite suppressing agents including phentermine, fenfluramine and
dexfenfluramine are increasingly being used for the treatment of obesity.
Phentermine is chemically related to the amphetamines and shares their
potential for drug dependence and exacerbation of cardiovascular problems.
Fenfluramine and dexfenfluramine are not amphetamine-like, but have been
associated with rare cases of unexplained ("primary") pulmonary hypertension,
some fatal. This case-control study was designed to look at risk factors
for the development of primary pulmonary hypertension, in particular in
relation to the use of anorexic drugs.

Methods

Cases: Cases were prospectively and actively recruited from hospitals
in four countries (France, Belgium, the United Kingdom and the Netherlands)
and were considered if the diagnosis of pulmonary hypertension was first
made by right heart catheterization between September 1, 1992 and September
30, 1994. Patients with secondary pulmonary hypertension were excluded.
In Belgium, an attempt was made to find all new cases of primary
pulmonary hypertension, allowing calculation of incidence.

Controls: Four controls were selected for each case from the medical
practice of the case patient's general practitioner and matched for sex,
age and number of visits per year (greater than or less than two per year).
When the case patient's GP could not serve as a source of controls, a physician
practicing in the same region was used.

Exposures: Detailed, face to face interviews with cases and controls
were conducted by non medically trained interviewers who were unaware of
the study's hypothesis. Exposure to antihypertensive drugs, oral contraceptives,
thyroid extract and anorexic drugs was determined. The anorexic drugs examined
were fenfluramine, dexfenfluramine and several amphetamine-like agents
(diethylpropion, clobenzorex, fenproporex, mazindol and phenmetrazine).
The index date for determining exposure was the first onset of symptoms
(this same date was then used for each case patient's corresponding controls);
exposures were only considered if they occurred before the index date and
were classified as recent (within 12 months prior to the index date) or
"past use" (greater than 12 months prior to the index date).

Results

Case patients: A total of 95 patients were included in this study,
80 with definite and 15 with probable primary pulmonary hypertension. The
female:male ratio was 2.3:1, the mean age 44.7 years. 91% presented with
dyspnea, severe in 2/3. Time from symptom onset to diagnosis was greater
than one year in 2/3 of patients.

Two patients reported a family history of primary pulmonary hypertension,
three had HIV (without AIDS), seven reported a history of cirrhosis, confirmed
in four. None of these were found in the controls.

Appetite-suppressant use: Among the 95 case patients, 31.6% reported
definite use of appetite suppressants before the index date, vs. 7.3% among
the 355 controls. This yielded an adjusted odds ratio of 6.3 (adjusted
for multiple risk factors including use of cocaine, smoking and high body-mass
index).

For recent use (within 1 year prior to the index date) the OR was
10.1, for past use only 2.4.

Use of anorexic drugs for less than 3 months was associated with an
OR of only 1.8 (not significant). Use of appetite suppressant drugs for
greater than 3 months (the principal outcome of this study) was associated
with an adjusted odds ratio of 23.1.

When case patients with a family history, a history of cirrhosis, HIV
or IV drug use were excluded, the adjusted OR increased slightly, to 8.6.

Incidence estimate: From the Belgian data, where all incident cases
of newly diagnosed primary pulmonary hypertension were assumed to have
been captured, the incidence of the disease was estimated at 1.7 per million
inhabitants per year.

Authors' Discussion

In their discussion, the authors review a number of potential sources
of bias and confounding.

Patients with pulmonary hypertension might be more likely to remember exposure
than controls (recall bias). However, the use of these agents among controls
was close to what sales figures would have predicted.

Patients using anorexic agents might be more likely to have their disease
discovered earlier, due to closer surveillance. This is unlikely, since
the time from symptom onset to diagnosis was similar in the two groups.

If the disease had actually begun earlier than assumed, some of the exposures
might not have antedated the disease onset and thus would not have been
true exposures. The authors recalculated their results moving the index
date back twelve months, which actually increased the odds ratio slightly.

Finally, adjusting for obesity, a possible confounder, did not alter the
results.

The authors conclude that their results are unlikely to be the result of
chance or bias, and that the increased risk of pulmonary hypertension with
use of anorexic agents for periods longer than one year might even be higher;
not enough data are available yet to answer this question. Also, there
is not enough data to speculate on whether these results apply only to
the derivates of fenfluramine or to other appetite suppressing drugs as
well.

Editorial

An editorial (complete
text from NEJM) by Drs. JoAnn Manson and Gerald Faich argues that the
risk of primary pulmonary hypertension must be balanced against the health
risks of obesity. They go on to estimate the risk-benefit ratio in the
following fashion:

From the Nurses' Health Study (Dr. Manson was lead author), the risk of
death among those with body-mass indexes between 29 and 32 was 60 to 70
percent higher than among those with BMI's between 25 and 27. This yielded
1260 excess lives lost per million women per year due to obesity.

A 12-month trial of dexfenfluramine yielded specific values for weight
loss achieved among the participants.

Applying these values for weight loss achieved to the excess mortality
observed in the Nurses' Health Study yielded 280 deaths prevented per million
obese persons treated with dexfenfluramine per year.

Assuming a background risk of 1.2 cases of primary pulmonary hypertension
and an increase in risk with dexfenfluramine treatment of 23, there would
be about 28 cases per million of PPH caused by use of this agent; assuming
a mortality rate of 50% for the disease, there would be 14 deaths caused
by dexfenfluramine per million patients treated. This yields a benefit:risk
ratio of 280 lives saved for 14 deaths caused, or 20:1.

Comment

The study presented here seems well designed and documents a significant
increase in a small baseline risk of "primary" pulmonary hypertension,
caused by the use of appetite suppressant drugs. What the risk will be
when these agents are used for periods longer than a year remains to be
seen. Also, too few patients used only the amphetamine-like preparations
to make any statements about them. To my knowledge, they have not yet been
linked to pulmonary hypertension. Undetected selection bias is always a
risk with case-control studies. The actual risk associated with the use
of these agents could, thus, be somewhat higher or lower.

The editorial has generated controversy, reported in the media, because
its authors have had financial ties to the pharmaceutical industry producing
these drugs. This issue aside, I believe that the analysis presented in
the editorial, which yielded a benefit:risk ratio of 20:1 is problematic,
for a number of reasons.

The number of deaths that can be prevented by weight loss was obtained
by looking at the excess mortality due to obesity found in the Nurses'
Study and assuming that these excess deaths could be prevented by weight
loss. This is not a reasonable assumption. To take an example from another
domain, ventricular ectopy post-myocardial infarction is associated with
a higher death rate in the year post-MI. Suppressing VPC's however, with
certain medications turned out to increase mortality in the CAST study
(presumably through pro-arrhythmia). By analogy, what counts is not the
excess mortality due to obesity but the decrease in mortality that can
actually be obtained through weight loss.

One of the very few studies that prospectively looked at the change
in mortality associated with voluntary weight loss (the above-cited AJE
article) did, in fact, find that weight loss was associated with a 20%
decrease in all-cause mortality, but only in subjects with obesity-related
co-existing conditions. When all-comers were looked at, those with and
without co-existing medical problems, the mortality was decreased by about
800 per million person-years (by my calculations from the article), less
than the 1260 assumed in the editorial.

Even assuming a significant decrease in mortality from intentionally lost
weight, as shown in the study from the AJE, the method of weight loss in
that study was not through derivates of fenfluramine but, presumably, in
large part from diet and exercise. Diet and exercise provide additional
health benefits which may not be matched, "pound for pound" by weight loss
using anorexic agents. We cannot simply extrapolate the benefits of weight
loss through lifestyle modification to weight loss using drugs.

Finally, the excess mortality of 14 per million person years quoted here
could increase if these agents are used for longer periods of time. Currently,
dexfenfluramine is only FDA approved for treatment up to one year.

Thus, although there may well be an overall benefit to the use of anorexic
agents, especially in patients with risk factors for obesity-related diseases,
the risk:benefit estimate provided in the editorial seems optimistically
biased.

Randomized trials looking at these drugs vs. placebo, and at different
drugs taken for different periods of time are needed soon, since the public
demand for these medications is likely to increase rapidly. In the absence
of randomized trials, close surveillance of patients receiving these agents
for prolonged periods of time will be essential. Perhaps a national registry
should be considered.

9/1/96

Reader comments

The New England Journal of Medicine has published an editorial
piece about the conflict of interest issue related to the editorial
about this study. The authors of that editorial respond in a letter
to the editor.